Monocyte-released HERV-K dUTPase engages TLR4 and MCAM causing endothelial mesenchymal transition
| Autor: | Marlene Rabinovitch, Toshie Saito, Maria Eugenia Ariza, Shoichiro Otsuki, Jan-Renier A. J. Moonen, Lingli Wang, Aiqin Cao, David Marciano, Dan Li, Shalina Taylor, Rebecca L. Harper |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Epithelial-Mesenchymal Transition
Slug viruses Endothelial cells Hypertension Pulmonary Inflammation CD146 Antigen Pulmonary Artery Monocytes Proinflammatory cytokine Mice Downregulation and upregulation Vascular Biology medicine Animals Pyrophosphatases Receptor biology Chemistry Monocyte Macrophages Endogenous Retroviruses General Medicine biology.organism_classification Cell biology medicine.anatomical_structure embryonic structures TLR4 Snail Family Transcription Factors Signal transduction medicine.symptom Research Article Signal Transduction |
| Zdroj: | JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | We previously reported heightened expression of the human endogenous retroviral protein HERV-K deoxyuridine triphosphate nucleotidohydrolase (dUTPase) in circulating monocytes and pulmonary arterial (PA) adventitial macrophages of patients with PA hypertension (PAH). Furthermore, recombinant HERV-K dUTPase increased IL-6 in PA endothelial cells (PAECs) and caused pulmonary hypertension in rats. Here we show that monocytes overexpressing HERV-K dUTPase, as opposed to GFP, can release HERV-K dUTPase in extracellular vesicles (EVs) that cause pulmonary hypertension in mice in association with endothelial mesenchymal transition (EndMT) related to induction of SNAIL/SLUG and proinflammatory molecules IL-6 as well as VCAM1. In PAECs, HERV-K dUTPase requires TLR4-myeloid differentiation primary response-88 to increase IL-6 and SNAIL/SLUG, and HERV-K dUTPase interaction with melanoma cell adhesion molecule (MCAM) is necessary to upregulate VCAM1. TLR4 engagement induces p-p38 activation of NF-κB in addition to p-pSMAD3 required for SNAIL and pSTAT1 for IL-6. HERV-K dUTPase interaction with MCAM also induces p-p38 activation of NF-κB in addition to pERK1/2-activating transcription factor-2 (ATF2) to increase VCAM1. Thus in PAH, monocytes or macrophages can release HERV-K dUTPase in EVs, and HERV-K dUTPase can engage dual receptors and signaling pathways to subvert PAEC transcriptional machinery to induce EndMT and associated proinflammatory molecules. |
| Databáze: | OpenAIRE |
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